Enhancing Respiratory Motor Function after Spinal Cord Injury

增强脊髓损伤后的呼吸运动功能

• 批准号: 10323658
• 负责人: Carlos B Mantilla
• 金额: $ 57.82万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323658
• 关键词: Affect; Behavior; Brain-Derived Neurotrophic Factor; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Contralateral; Coughing; Data; Dependence; Development; Fatigue; Future; Glutamates; Hypercapnia; Hypoxia; Impairment; Injury; Ipsilateral; Laboratories; Measures; Mechanical ventilation; Mediating; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Muscle; N-Methylaspartate; Nerve; Neuronal Plasticity; Paralysed; Pathway interactions; Patients; Persons; Presynaptic Terminals; Rattus; Recovery; Research; Resistance; Respiratory Diaphragm; Respiratory physiology; Role; Signal Transduction; Sneezing; Spinal; Spinal cord injury; Synapses; Time; United States; base; density; gain of function; knock-down; loss of function; mRNA Expression; mortality; neurotransmission; novel therapeutics; overexpression; postsynaptic; presynaptic; receptor; receptor expression; recruit; respiratory; small hairpin RNA; therapeutically effective; ventilation

ABSTRACT The proposed studies exploit exciting new developments in neuroplasticity to enhance recovery of ventilatory- related diaphragm muscle (DIAm) activity following cervical spinal cord injury. There are nearly 17,000 new cases of spinal cord injury in the United States each year, with around 282,000 people affected. The majority of these injuries involve the cervical spinal cord and result in significant impairment of ventilatory-related DIAm activity and an inability to maintain adequate ventilation. Long-term dependence on mechanical ventilation is associated with significant morbidity and mortality. Thus, enhancing recovery of ventilatory-related DIAm activity following cervical spinal cord injury is highly significant. Upper-cervical (C1-C3) spinal cord injury disrupts direct excitatory descending bulbospinal glutamatergic (Glu) input to phrenic motor neurons (PhMNs). Importantly, most spinal cord injuries are incomplete, thus spared descending pathways to PhMNs are an extant substrate for neuroplasticity to restore DIAm activity, either by increasing excitatory (Glu) nerve terminal density and/or by altering postsynaptic Glu receptor (NMDA NR1) expression. In the proposed studies, we will employ a well-established C2 spinal hemisection (C2SH) model of incomplete spinal cord injury in rats, in which spontaneous recovery of ventilatory-related DIAm activity occurs in a BDNF/TrkB signaling-dependent fashion. Previously, we found that C2SH impairs ventilatory-related DIAm behaviors, which require recruitment of smaller (more excitable) PhMNs comprising fatigue resistant motor units. These ventilatory-related behaviors only partially recover over time, whereas, surprisingly, there is near full recovery of higher force airway clearance behaviors, which require recruitment of larger (less excitable) PhMNs comprising more fatigable motor units. The overall hypothesis of the proposed research is that the mechanisms underlying neuroplasticity and recovery of ventilatory-related DIAm activity after C2SH depend on PhMN size (more pronounced in smaller PhMNs), are mediated by NMDA Glu neurotransmission, and are promoted by BDNF/TrkB signaling. Three specific aims are proposed: 1) To determine the effect of BDNF/TrkB signaling on Glu presynaptic terminal density at PhMNs of differing size after C2SH; 2) To determine the effect of BDNF/TrkB signaling on NMDAR expression at PhMNs of differing size after C2SH; and 3) To determine whether NMDARs underlie the effects of BDNF/TrkB signaling on recovery of ventilatory-related DIAm activity after C2SH. The results of the proposed studies will guide development of effective therapeutic approaches to enhance recovery of respiratory function in patients with incomplete spinal cord injury.

摘要 这项研究利用了神经可塑性方面令人兴奋的新进展，以促进恢复性记忆。 相关的膈肌（DIAm）活动后，颈脊髓损伤。新增近17,000个 在美国，脊髓损伤的病例每年约有28.2万人受到影响。大多数 这些损伤涉及颈脊髓，并导致与呼吸机相关的DIAm严重受损 活动和无法保持足够的通风。长期依赖机械通气是 与显著的发病率和死亡率相关。因此，促进呼吸机相关DIAm的恢复 颈脊髓损伤后的活动是非常重要的。上颈段（C1-C3）脊髓损伤 破坏对膈运动神经元（PhMN）的直接兴奋性下行球脊髓谷氨酸能（Glu）输入。 重要的是，大多数脊髓损伤是不完全的，因此保留的PhMN下行通路是一个重要的机制。 神经可塑性的现存底物，以恢复DIAm活性，或者通过增加兴奋性（Glu）神经末梢 密度和/或通过改变突触后Glu受体（NMDA NR1）表达。在建议的研究中，我们会 采用大鼠中成熟的C2脊髓半切（C2SH）不完全脊髓损伤模型， 呼吸机相关DIAm活性的自发恢复发生在BDNF/TrkB信号依赖性 时尚.以前，我们发现C2SH损害呼吸机相关的DIAm行为，这需要招募 包括抗疲劳运动单元的更小（更易兴奋）的PhMN。这些与呼吸机有关的 随着时间的推移，行为只能部分恢复，而令人惊讶的是，更高的力量几乎完全恢复 气道清除行为，其需要募集较大（较不兴奋）的PhMN， 易疲劳的运动单位这项研究的总体假设是， C2SH后神经可塑性和呼吸相关DIAm活性的恢复取决于PhMN大小（更多 在较小的PhMN中明显），由NMDA Glu神经传递介导，并由 脑源性神经营养因子/TrkB信号传导。提出了三个具体目标：1）确定BDNF/TrkB信号转导对 C2SH后不同大小PhMN的Glu突触前终末密度; 2）为了确定C2SH后不同大小PhMN的Glu突触前终末密度的影响， BDNF/TrkB信号传导对C2SH后不同大小的PhMN处NMDAR表达的影响;以及3）为了确定 NMDAR是否是BDNF/TrkB信号对呼吸机相关DIAm活性恢复的影响的基础 在C2SH之后。拟议研究的结果将指导开发有效的治疗方法， 促进不完全性脊髓损伤患者呼吸功能的恢复。